Despite the numerous biomarkers reported, few are useful for predicting metastasis. In our recent studies, we have uncovered a novel splice isoform of the prohormone processing enzyme, carboxypeptidase E (CPE-deltaN) that is elevated in metastatic hepatocellular, colon, breast, head and neck carcinoma cells. CPE-deltaN lacks the N-terminus that is normally present in secretory granule wild-type CPE, and is localized to the nucleus of metastatic cancer cells. Overexpression of CPE-deltaN in hepatocellular carcinoma (HCC) cells promoted their proliferation and migration by up-regulating expression of a metastasis gene via epigenetic mechanisms. SiRNA knockdown of CPE-deltaN expression in highly metastatic HCC cells inhibited their growth and metastasis in nude mice. In retrospective clinical studies, CPE-deltaN mRNA quantification in primary HCC from patients established a cut off level, above which predicted future metastasis within 2 years with high sensitivity and specificity and independent of cancer stage. Furthermore, in a prospective clinical study on patients with pheochromocytoma/paragangliomas, we were able to predict with high accuracy from the mRNA copy numbers of CPE-deltaN in the resected tumors, those patients who would develop future metastasis, although they were diagnosed with benign tumors at the time of surgery. Additionally, we showed that CPE-delta N is also an excellent biomarker for diagnosis of metastatic colon rectal cancer. Thus, CPE-deltaN is a novel tumor inducer and a powerful prognostic marker for predicting future metastasis in different cancers, superior to histopathological diagnosis.